To better understand cellular signaling in the human immune system and innate immunity across a broad spectrum of organisms, the investigator plans to develop, analyze, and test mathematical models for signal transduction mediated by the interleukin-1 (IL-1) type 1 receptor (IL-1R1). This receptor is a relatively well-studied member of the IL-1 R/Toll-like receptor (TLR) superfamily of transmembrane proteins that share homology with Toll in Drosophila. These proteins are involved in responding to injury or infecti6n. IL-1 R1 is involved in inflammatory responses, and TLRs recognize an array of endogenous and microbial molecules, such as lipopolysaccharide, and regulate immune responses to infection. Receptors of the IL-1R and TLR families, and related signaling proteins in invertebrate animals and plants, share similar mechanisms of signal transduction. The evolutionarily conserved, cytoplasmic TolI/IL-1 receptor (TIR) domain [55] plays an essential role in signaling: upon ligand stabilization of homo- or hetero-oligomers of receptors, TIR domains provide binding sites for cytosolic adapter proteins that interact with serine/threonine kinases to initiate an intracellular cascade of signaling reactions. Specific Aim 1. Development and computational analysis of mathematical models for early membrane proximal events in IL-1R1-mediated signal transduction that track the interactions of multiple components of the signal transduction apparatus and that predict the outcome of deletion, overexpression, or molecular modification of any of these components. Specific Aim 2. Identification of general principles of TIR receptor signal transduction through the study of relatively simple mathematical models for phenomena considered in models of Specific Aim 1.